The known compound, cromolyn sodium (sodium cromoglycate, SCG) has the property that it inhibits the release of allergic mediators from sensitized tissues but does not interfere with the combination of antigen and antibody. However, this prior art compound has the disadvantage that it has been found to lack oral activity.
The present invention relates to new heterocyclic nitrogen compounds that are useful as pharmacological agents and to methods of their synthesis. More particularly, the compounds of the present invention are trans-2,3b,4,5,7,8b,9,10-octahydronaphto [1,2-c:5,6-c']dipyrazoles which may be substituted in both of the pyrazole rings. The compounds of the present invention are useful as orally active anaphylactic inhibitors for the treatment of asthmatic symptoms.
The compounds which are the subject of the present invention are represented by the formula: ##STR1## wherein R is H, OH, CN, CO.sub.2 Me, CO.sub.2 Et, CO.sub.2 H, CF.sub.3, halogen, NO.sub.2, or NH.sub.2. These groups in general tend to increase or enhance the hydrogen-bonding capacity of the pyrazole hydrogen, a fact that is related to the biological properties of these molecules. In fact, removal of the pyrazole hydrogen by appropriate substitution eliminates completely the biological activity.
The octahydronaphto[1,2-c:5,6-c']dipyrazoles of the present invention wherein R is H, OH, CN, CO.sub.2 Et, CO.sub.2 Me, CO.sub.2 H or CF.sub.3 may be produced by reacting the corresponding trans-2,6-bis(hydroxymethylene)decalin-1,5-dione of the formula: ##STR2## wherein R is as above defined, with more than two equivalents of hydrazine in refluxing ethanol for 6 hrs.
In the case of the present compounds wherein R is halogen or NO.sub.2, these groups are introduced after formation of the parent compound of formula (1), (R = H) by appropriate substitution. Once the NO.sub.2 analog is obtained, the amino (NH.sub.2) compound will also be obtainable by catalytic reduction.
The starting materials designated in formula (2) herein are also considered novel and can be obtained from known trans-decalin-1,5-dione by reaction under nitrogen with an excess of the corresponding ester of the formula: EQU R--CO.sub.2 R' (3)
wherein R is equal to H, OMe, OEt, CN, CO.sub.2 Me, CO.sub.2 Et, or CF.sub.3 and R' is Me or Et, in the presence of sodium methoxide as catalyst and dry pyridine as solvent. The known trans-decalin-1,5-dione may be obtained by starting with commercially available 1,5-decalindiol which is subjected to oxidation under the conditions reported by W. S. Johnson et al. J. Amer. Chem. Soc., 73,5464 (1951). As reported by these authors, the resulting dione is equilibrated to its most stable trans isomer and obtained as pure trans-decalin-1,5-dione.